Malignant Pleural Mesothelioma: Update on Treatment Options with a Focus on Novel Therapies

Section of Interventional Pulmonology and Thoracic Oncology, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, 833 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
Clinics in chest medicine (Impact Factor: 2.07). 03/2013; 34(1):99-111. DOI: 10.1016/j.ccm.2012.12.005
Source: PubMed


There is evidence that improved treatments of malignant pleural mesothelioma are increasing the quality and quantity of life for patients with mesothelioma. Multimodality treatment programs that combine maximal surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of patients with mesothelioma. Lung-sparing surgery may allow improvements in pulmonary function after surgery-based multimodality therapy, and potential longer overall survival than that seen with extrapleural pneumonectomy. Experimental treatments provide hope for all patients with mesothelioma, and in the future may be combined with standard therapy in multimodality protocols.

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    • "Malignant mesothelioma (MM) originates from the thin monolayer of mesothelial cells, lining the body cavities and surface of internal organs. It can arise in the pleural cavity, peritoneal cavity, pericardial cavity or tunica vaginalis, but pleural cavity is most frequently involved (~80%) [1]. A study based on WHO mortality database reported a death toll of 92,253 from MM within 1994-2008 in 83 countries [2] and global cases of MM are projected to be on the rise for decades to come [3]. "
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    ABSTRACT: Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. Upon fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasome in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-β pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP1 as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still ~8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by β-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease. (245 words). Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 05/2015; 86. DOI:10.1016/j.freeradbiomed.2015.05.002 · 5.74 Impact Factor
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    • "The reported range for median survival for pleural mesothelioma in a 2009 review, regardless of stage, was between 9 and 17 months [33]. Other more recent reviews show no improvement in survival compared to this review [34] [35]. Our data are consistent with, but at the upper end of, median survival values reported by other studies for both peritoneal and pleural cases, suggesting that newer therapies do improve survival. "
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    ABSTRACT: Survival for mesothelioma has been shown to be poor, with marginal improvement over time. Recent advances in the understanding of pathophysiology and treatment of mesothelioma may impact therapy to improve survival that may not be evident from available clinical trials that are often small and not randomized. Therapies may affect survival differently based on mesothelioma location (pleural vs peritoneal). Data are conflicting regarding the effect of asbestos exposure on mesothelioma location. We examined survival in a large cohort of mesothelioma subjects analyzed by tumor location and presence and mode of asbestos exposure. Data were analyzed from cases (n = 380) diagnosed with mesothelioma from 1992 to 2012. Cases were either drawn from treatment referrals, independent medical evaluation for medical legal purposes, or volunteers who were diagnosed with mesothelioma. Subjects completed an occupational medical questionnaire, personal interview with the examining physician, and physician review of the medical record. This study reports better survival for mesothelioma than historical reports. Survival for peritoneal mesothelioma was longer than that for pleural mesothelioma (hazard ratio = 0.36, 95% confidence interval = 0.24-0.54, P < .001) after adjusting for gender and age at diagnosis. Non-occupational cases were more likely to be 1) diagnosed with peritoneal mesothelioma, 2) female, 3) exposed, and 4) diagnosed at a younger age and to have a 5) shorter latency compared to occupational cases (P < .001). Peritoneal mesothelioma was more likely associated with non-occupational exposure, thus emphasizing the importance of exposure history in enhancing early diagnosis and treatment impact. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.
    Translational oncology 02/2015; 8(1):35-9. DOI:10.1016/j.tranon.2014.12.002 · 2.88 Impact Factor
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    • "therapeutic strategies are urgently needed to improve outcomes (Astoul et al, 2012; Haas and Sterman, 2013). CD26 is a 110-kDa, type II transmembrane glycoprotein with known dipeptidyl peptidase IV (DPPIV) (DPPIV, EC activity in its extracellular domain and is capable of cleaving N-terminal dipeptides with either L-proline or L-alanine at the penultimate position (Ohnuma et al, 2008). "
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    ABSTRACT: Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. Methods: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. Results: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. Conclusions: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.
    British Journal of Cancer 04/2014; 110(9). DOI:10.1038/bjc.2014.151 · 4.84 Impact Factor
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